The Obesity Paradox in Patients With Peripheral Arterial Disease

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CHEST CHEST

Original Research Research Original COPD COPD

The Obesity Obesity Paradox Patients With With The Paradox in in Patients Peripheral Arterial Arterial Disease* Disease* Peripheral Wael Galal, Galal, MD; MD; Yvette Yvette R. B. M. van Gestel, Gestel, MSc; Wael R. B. M. van MSc; Sanne Sanne E. E. Hoeks, Hoeks, MSc; MSc; D. Sin, Sin, MD, MD, FCCP; FCCP; Tamara Tamara A. A. Winkel, Winkel, MD; MD; Jeraen J. Bax, Bax, MD; MD; Don Jeraen J. Don D. Hence Verhagen, Verhagen, MD; M. Awara, Awara, MD; MD; Jan Hence MD; Adel Adel M. M. M. Jan Klein, Klein, MD; MD; Ron T. van Domburg, Domburg, PhD; PhD; and and Don Don Poldermans, Poldermans, MD MD Ron T. van

Background: Cardiac Cardiac events events are are the the predominant predominant cause cause of of late late mortality mortality in in patients patients with with peripheral peripheral Background: arterial disease disease (PAD). (PAD). In In these these patients, patients, mortality mortality decreases decreases with with increasing increasing body body mass mass index index (BMI). (BMI). arterial COPD COPD is is identified identified as as aa cardiac cardiac risk risk factor, factor, which which preferentially preferentially affects affects underweight underweight individuals. individuals. Whether or or not not COPD COPD explains explains the the obesity obesity paradox paradox in in PAD patients is is unknown. unknown. Whether PAD patients Methods: We We studied studied 2,392 2,392 patients patients who who underwent underwent major major vascular vascular surgery surgery at at one one teaching teaching Methods: institution. Patients Patients were were classified classified according according to to COPD COPD status status and and BMls BMls (ie, (ie, underweight, underweight, normal, normal, institution. overweight, and and obese), obese), and and the the relationship relationship between between these these variables variables and and all-eause all-eause mortality overweight, mortality was was determined using using aa Cox regression analysis. analysis. The The median median follow-up follow-up period period was was 4.37 4.37 years years (interquar(interquardetermined Cox regression range, 1.98 1.98 to to 8.47 tile range, 8.47 years). years). tile Results: The The overall overall mortality mortality rates rates among among underweight, underweight, normal, normal, overweight, overweight, and and obese obese patients patients were were Results: 54%,50%,40%, and and 31%, 31%, respectively respectively (p (p < < 0.001). 0.001). The The distribution distribution of of COPD COPD severity severity classes classes showed showed 54%,50%,40%, an increased increased prevalence prevalence of of moderate-to-severe moderate-to-severe COPD COPD in in underweight underweight patients. patients. In In the the entire entire an population, BMI BMI (continuous) (continuous) was was associated associated with with increased increased mortality mortality (hazard (hazard ratio ratio [1m], [1m], 0.96; 0.96; 95% population, 95% confidence interval [CI], [CI], 0.94 0.94 to to 0.98). 0.98). In In addition, addition, patients patients who who were were classified classified as as being being underweight underweight confidence interval were at at increased increased risk risk for for mortality mortality (Im, (Im, 1.42; 1.42; 95% 95% CI, CI, 1.00 1.00 to after adjusting adjusting for for COPD COPD were to 2.01). 2.01). However, However, after severity the the relationship relationship was was no no longer longer significant significant (Im, (Im, 1.29; 1.29; 95% 95% CI, CI, 0.91 to 1.93). 1.93). severity 0.91 to Conclusions: The The excess excess mortality mortality among among undmweight undmweight patients patients was was largely largely explained explained by the overrepreoverrepreConclusions: by the of individuals individuals with with moderate-ta-severe moderate-to-severe COPD. COPD. COPD COPD may may in in part part explain explain the the "obesity "obesity paradox" paradox" sentation of sentation in the the PAD PAD population. population. (CHEST 2008; 2008; 134:925-000) in (CHEST 134:925-000) Key words: Key words: body body mass mass index; index; COPD; COPD; mortality; mortality; peripherul peripheml arterial arterial disease disease Abbreviations: ACE = angiotensin-converting enzyme; BMI = body body mass Abbreviations: ACE = angiotensin-mnverting enzyme; BMI = mass index; index; CI CI = heart HR = = hazard ratio; PAD PAD = = peripheral peripheral arterial arterial disease mellitus; mellitus; HF HF = heart failure; failure; HR hazard ratio; disease

Cardiac events events are are the the predominant predominant cause cause of of late Cardiac late mortality peripheral arterial arterial mortality in in patients patients with with peripheral disease (PAD).1-3 (PAD).1-3 Interestingly, Interestingly, in in this this population, population, disease the situation situation in in the the general general population, population, papaunlike the unlike tients who who are are obese better tients obese or or overweight overweight have have better survival rates rates than than those those patients patients who who are are of of normal normal survival weight."4 Indeed, Indeed, the the greatest greatest mortality mortality rates rates are are weight. observed in in patients patients who who are are underweight. underweight. This This observed phenomenon has has been been referred referred to to as as the the "obesity "obesity phenomenon paradox."4,5 To the reasons reasons underlying underlying the the paradox."4,5 To date, date, the obesity paradox paradox have have not not been been fully fully elucidated. elucidated. Over Over obesity the past past decade, decade, COPD COPD has has emerged emerged as indepenthe as an an independent dent risk risk factor factor for for cardiovascular cardiovascular mortality.6,7 mortality.s-? The The effects of of COPD COPD on on cardiovascular are amplified amplified effects cardiovascular risk risk are the presence presence of of another another cardiac cardiac risk risk factor factor (eg, in the (eg, in www.cbestlournal.orq www,chestjournal.org

= confidence = mnfidence

interval, inteIVa!; DM DM

= diabetes = diabetes

smoking, hypercholesterolemia, hypercholesterolemia, or In this smoking, or PAD). PAD). 88 In this study, we we investigated investigated the the influence influence of of COPD COPD on on the the study,

For editorial editorial comment comment see see page page 896 896 For relationship between between body body mass mass index index (BM!) (BM!) and and relationship mortality in in aa group group of of patients patients with with PAD.9 PAD.9 mortality

MATERIALS AND AND METHODS METHODS MATERIALS

We who were were We studied studied 2,392 2,392 consecutive consecutive adult adult surgical surgical patients patients who admitted to to the the Department Department of of Vascular of Erasmus Va~cular Surgery Surgery of Erasmus admitted University Medical Center Netherlands) between between Center (Rotterdam, (Rotterdam, the the Netherlands) University Medical January 1990 and November November 2006. 2006. Patients Patients were were evaluated evaluated for for the the January 1990 and presence and of COPD COPD prior prior to presence and severity severity of to their their surgical surgical intervention intervention CHEST // 134/5/ 134/5/ NOVEMBER, NOVEMBER, 2008 2008 CHEST

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using spirometry. spirometry. Vascular Vascular surgical surgical interventions interventions included included abdomiabdomiusing surgery, carotid carotid endarterectomy, endarterectomy, or or lower lower limb limb arterial arterial nal aortic aortic surgery, nal procedures. tlMI tlMI was was measured measured during during preoperapreoperarevascularization procednres. revascularization tive evaluation evaluation using using standard standard procedures. procedures. Ethics Ethics approval approval for for data data tive collection and and cohort cohort evaluation evaluation were were obtained obtained from from the the Medical Medical collection Ethics Committee Committee of of the the hospital. hospital. Ethics Baseline data data included included age, age, height, height, weight, weight, and and recorded recorded Baseline history. The The National National Institutes Institutes of of Health Health obesity obesity classiclassimedical history. medical 10 was was used used to to divide divide the the study study population population into into the the fication 10 fication < 18.5 18.5 kglm kglm 22 );) ; following four four BMI BMI categories: categories: underweight underweight (BMI (BMI < following normal weight weight (BMI, (BMI, 18.5 18.5 to to 24.9 24.9 kglm kglm2);) ; overweight overweight (BMI, (BMI, 25 25 to to normal 29.9 kglm kglm2);) ; and and obese obese (BMI (BMI 2: 2: 30 30 kglm kglm2).) . The The number number of of 29.9 patients studied studied in in each each of of these these groups groups was was 63 63 (2%), (2%), 1,101 1,101 patients (33%),956 (28%), (28%), and and 272 272 (8%), (8%), respectively. respectively. We We differentiated differentiated (33%),956 the patients patients according according to to whether whether they they had had COPD COPD (n == 1,110; 1,110; the or did did not not have have COPD COPD (n == 1,282; 1,282; 5:3.6%) 5:3.6%) based based on on the the 46.4%) or 46.4%) definition of of the the Global Global Initiative Initiative for for Chronic Chronic Obstructive Obstructive Lung Lung definition Disease (or (or GOLD) GOLD) Committee Committee (FEV/FVC (FEV/FVC ratio l'tKio following following Disease therapy with with bronchodilators bronchodilators and and symptoms symptoms of of cough cough or or dyspnea, dyspnea, therapy < 70%). 70%). Mild Mild COPD COPD was was defined defined as as an an FEV! FEV! of of 2: 2: 80% 80% prepre< dicted; moderate moderate COPD COPD was was defined defined as as an an FEV] FEV] of of 2: 2: 50% 50% to to dicted; < 80% 80% predicted; predicted; and and severe severe COPD COPD was was defined defined as as an an FEV! FEV! of of < ll We < ,50% ,50% predicted. predicted.': We considered considered patients patients without without COPD COPD as as < those without without pulmonary pulmonary function function tests, tests, those those without without symptoms symptoms (ie, (ie, those without pulmonary pulmonary complaints complaints and/or and/or pulmonary pulmonary medications), medications), and and without normal arterial arterial blood blood gas gas levels levels (Pco (Pco,2 < < 6.4 6.4 kPa; kPa; those who who had had nonnal those POo > > 10.0 10.0 kPa) kPa) at at the the time time of of assessment. assessment. POo Cardiac medical medical history history included included details details of of previous previous myocardial myocardial Cardiac heart failure failure (HF), (HF), and and coronary coronary infarction, angina angina pectoris, pectoris, heart infarction, artery revascularization revascularization (ie, tie, percutaneous percutaneous coronaIy coronaIy intervention intervention artery or coronary coronary artery artery bypass bypass grafting). grafting). Comorbidities Comorbidities reported reported in in the the or medical history history included included diabetes diabetes mellitus mellitus (DM), (DM), hypertension, hypertension, medical smoking, dyslipidemia, dyslipidemia, and and renal renal dysfunction. dysfunction. DM DM was was defined defined as as smoking, fasting glucose glucose concentration concentration of of 2: 2: 7.0 7.0 mmoVL mmol/L or or the the use use of of aa aa fasting hypoglycemic agent. agent. Hypertension Hypertension was was defined defined as as aa BP BP of of hypoglycemic 2: 140/90 140/90 mm mm Hg Hg or or the the use use of of antihypertensive antihypertensive medications. medications. A A 2: diagnosis of of HF HF was was considered considered if if the the patient patient had had aa history history of of diagnosis shortness of of breath breath on on exertion exertion or or at at rest, rest, decreased decreased physical physical shortness ability, swelling swelling of of lower lower limbs limbs on on physical physical examination, examination, and and ability, echocardiographic signs signs consistent consistent with with cardiac cardiac decompensadecompensaechocardiographic tion.'? Dyslipidemia Dyslipidemia was was defined defined as as aa fasting fasting serum serum total total cholescholestion.!2 *From the the Departments Departments of of Anesthesiology Anesthesiology (Drs. (Drs. Galal, Galal, Klein, Klein, and and *From Hocks), Surgery Surgery (Drs. (Drs. Poldermans, Ms. Ms. van van Gestel, Gestel, and and Ms. Ms. Hoeks), Poldermans, Winkel and and Verhagen), Verhagen), and and Cardiology Cardiology (Dr. (Dr. van van Domburg), Domburg), Winkel Erasmus Medical Medical Center, Center, Rotterdam, Rotterdam, the the Netherlands; Netherlands; the the Erasmus James Hogg Hogg iCAPTURE iCAPTURE Center Center for for Cardiovascular Cardiovascular and and PulmoPulmoJames nary Research Research (Dr. (Dr. Sin), Sin), St. St. Paul's Paul's Hospital Hospital & & University University of of nary Department of of British Columbia, Columbia, Vancouver, Vancouver, BC, BC, Canada; Canada; the the Department British Cardiology (Dr. (Dr. Bax), Bax), Leiden Leiden Medical Medical Centre, Centre, Leiden, Leiden, the the Cardiology Netherlands; and and the the Department Department of of Anesthesiology Anesthesiology (Dr. (Dr. Awara), Awara), Netherlands; Tanta Faculty Faculty of of Medicine, Medicine, Tanta, Tanta, Egypt. Egypt. Tanta Ms. van van Gestel Gestel and and Ms. Ms. Hoeks Hoeks are are supported supported by by an an wlrestricted unrestricted Ms. research grant grant from from the the foundation foundation "Lijf "Lijf en en Leven," Leven," the the Netherhmds. Netherlands. research Dr. Galal Galal has has received received aa postdoctoral postdoctoral research research scholarship scholarship to to Dr. study in in the the Netherlands. Netherlands. Ms. Ms. van van Gestel, Gestel, Ms. Ms. Hoeks, Hoeks, and and Drs. Drs. study Sin, \Vinkel, \Vinkel, Bax, Bax, Verhagen, Verhagen, Awara, Awara, Klein, Klein, van van Domburg, Domburg, and and Sin, Poldermans have have reported reported to to the the ACCP ACCP that that no no significant significant Poldermans conflicts of of interest interest exist exist with with any any companies/organizations companies/organizations whose whose conflicts products or or services services may may be be discussed discussed in in this this article. article. products Manuscript received received FebruaIY February 15, 15, 2008; 2008; revision revision accepted accepted June June 16, 16, Manuscript 2008. 2008. Reproduction of of this this article article is is prohibited prohibited without without written written pennission pennission Reproduction from the the American American College College of of Chest Chest Physicians Physicians (www.chestjoumal. (www.chestjoumal. from orglmiscireprints.shtml). orglmisclreprints.shtml). Correspondence to: to: Don Don Polderrnans, Poldermans, MD, MD, Erasmus Erasmus Medical Medical Correspondence Center, Gravendijkwal230, Gravendijkwal230, Room Room H-921, H-921, 3015 3015 CE CE Rotterdam, Rotterdam, Center, the Netherlands; Netherlands; e-l1wil: e-mail. [email protected] d.poldermansteerasmusmc.nl the DOl: 1O.1378/chest.08-0418 1O.1378/chest.08-0418 DOl: 926 926

terollevel of of 2: 2: 5.5 5.5 mmoVL, mmol/L, aa triglyceride triglyceride level level of of 2: 2: 1.7 1.7 mmoVL, mmol/L, terollevel or aa high-density high-density lipoprotein lipoprotein cholesterol cholesterol level level of of ~ 1.0 1.0 mmoVL mmol/L at at or assessment or or the the use use oflipid-Iowering oflipid-Iowering agents. agents. Renal Renal dysfunction dysfunction assessment was defined defined as as aa serum serum creatinine creatinine level level of of > > 2.0 2.0 mgldL mgldL (177 (177 was fJ-moVL) or or aa requirement requirement for for dialysis. dialysis. In In addition, addition, the the cardiac cardiac fJ-moVL) patient using using the the Lee Lee revised revised risk score score was was detennined determined for for each each patient risk cardiac risk risk index, index, which which included included information information about about vascular vascular cardiac operations, history history of of ischemic ischemic heart heart disease, disease, HF, HF, cerebrovascucerebrovascuoperations, lar accidents, accidents, insulin insulin therapy therapy for for DM, DM, and and renal renal disease disease with with aa lar > 2.0 2.0 mgldL.I:> mgldL.I:> Patients Patients were were assessed assessed serum creatinine creatinine level level of of > serum for the the use use of of cardiac cardiac medications medications including including l3-blockers, l3-blockers, statins, statins, for angiotensin-converting enzyme enzyme (ACE) (ACE) inhibitors, inhibitors, diuretics, diuretics, aspiaspiangiotensin-converting lin, anticoagulants, anticoagulants, nitrates, nitrates, and and calcium calcium channel channel blockers, blockers, The The lin, use of of pulmonary pulmonary medications, medications, including including bronchodilators bronchodilators and and use corticosteroids, was was also also captured. captured. '' corticosteroids,

Study End End Points Points Study The end end point point of of this this study study was was all-cause all-cause mortality. mortality. The The median median The duration of of follow-up follow-up was was 4.37 4.37 years years (interquartile (interquartile range, range, 1.98 1.98 to to duration 8.47 years). years). Information Information about about death death was was obtained obtained and and verified verified by by 8.47 reviewing the the hospital hospital record record and and linking linking with with the the national national civil civil reviewing registry, registlY·

Statistical Analysis Analysis Statistical Categoric variables variables are are expressed expressed as as percentages percentages and and were were Categoric compared using using aa Pearson Pearson X X22 test. test. Continuous Continuous variables variables are are compared presented as as the the mean mean (± (± SD) SD) and and were were compared compared using using analysis analysis presented of variance. variance. \Ve We performed performed univariate univariate and and multivariate multivariate analyses analyses of of of survival times times using using aa Cox Cox proportional proportional hazard hazard model model for for all-cause all-cause survival mortality from from which which hazard hazard ratios ratios (HRs) (HRs) and and 95% 95% confidence confidence mortality intervals (CIs) (CIs) were were derived. derived. In In the the regression regression analyses, analyses, we we used used intervals BMI both both as as aa continuous continuous variable variable and and as as aa categoric categoric variable. variable. BMI When the the categOlic categoric BMI BMI variable variable was was included included in in the the model, model, \Vhen patients with with normal normal weight weight were were taken taken as as the the reference reference group. group. patients In the the multivariate multivariate models, models, we we adjusted adjusted for for baseline baseline characterischaracterisIn tics including including age, age, gender, gender, cardiac cardiac risk risk score, score, current current smoking smoking tics status, COPD COPD severity, severity, year year of of surgery, surgery, and and use use of of pulmonary pulmonary status, medications. In In addition, addition, we we used used stepwise stepwise regression regression models models to to medications. the association association between between the the BMI BMI categories categories and and investigate the investigate mortality, with with stepwise stepwise adjustment adjustment made made for for clinical clinical variables variables mortality, and subsequently subsequently for for COPD COPD severity severity and and current current smoking. smoking. and Statistical significance significance was was defined defined as as aa pp value value of of < < 0.05. 0.05. All All Statistical statistical analysis analysis was was performed performed using using aa statistical statistical software software statistical 15.0 for for Windows; Windows; SPSS; SPSS; Chicago, Chicago, IL). IL). package (SPSS, (SPSS, version version 15.0 package

RESULTS RESULTS

In the the population population that that we we studied, studied, we we found found aa In relatively homogenous homogenous distribution distribution of of BMI BMI (mean (mean relatively BMI, 25.4 25.4 ± ± 4.0 4.0 kglm kglm22 ).) . Of Of the the 2,392 2,392 patients, patients, only only BMI, 2.6% were were underweight underweight and and 11.4% 11.4% were were obese, obese, 2.6% while the the majority majority was was either either normal normal (46%) (46%) or or while overweight (40%). (40%). Patient Patient characteristics characteristics according according overweight to BMI BMI classifications classifications are are presented presented in in Table Table 1. 1. to Current smokers smokers were were more more prominent prominent in in the the ununCurrent derweight group group (p (p = = 0.002). 0.002). Moderate-to-severe Moderate-to-severe derweight COPD was was more more frequent frequent among among underweight underweight papaCOPD tients (40%), (40%), while while the the frequencies frequencies of of COPD COPD in in the the tients overweight and and obese obese groups groups were were 25% 25% and and 22%, 22%, overweight respectively (p (p < < 0.001). 0.001). In In contrast contrast to to the the underunderrespectively Original Research Research Original

Table I-Baseline I-Baseline Clinical Clinical Characteristics Characteristics of of 2,392 2,392 Patients Patients According According to to BMI BMI Categories* Categories* Table Variables Variables Demographies Demographics Age,f yr yr Age,f Male gender gender Male Type of of surgery surgery Type

AAA AAA CEA CEA LLR LLR Cardiac history history Cardiac Myocardial infarction infarction Myocardial Revascularization tt Revascularization Heart failure failure Heart Angina Angina Clinical variables variables Clinical Hypertension Hypertension DM DM Current smoking smoking status status Current Dyslipidemia Dyslipidemia BMlt BMlt Renal dysfunction dysfunction Renal COPD COPD None None Mild Mild Moderate Moderate Severe Severe Cardiac medication medication Cardiac Statins Statins l3-blockers l3-blockers ACE inhibitors inhibitors ACE Calcium antagonists antagonists Calcium Diuretics Diuretics Aspirin Aspirin Anticoagulants Anticoagulants Nitrates Nitrates Pulmonary medication medication Pulmonary Bronchodilators Bronchodilators Corticosteroids Corticosteroids

Total Total (n = = 2,392) 2,392) (n

Underweight Group Group Underweight = 63) 63) (n = (n

Normal-Weight Group Group Normal-Weight (n = = 1,1(1) 1,1(1) (n

Overweight Group Group Overweight (n = = 9.56) 9.56) (n

Obese Group Group Obese (n = = 272) 272) (n

66 (11) (11) 66 1,782 (7.5) (7.5) 1,782

64 (14) (14) 64 34 (.54) (.54) 34

67 (11) (11) 67 823 (7.5) (7.5) 823

67 (10) (10) 67 749 (78) (78) 749

6:3 (11) (11) 6:3 176 (6.5) (6.5) 176

966 (40) (40) 966 ,561 (24) (24) ,561 86,5 (36) (36) 86,5

27 (43) (43) 27 (10) 66 (10) 30 (47) (47) 30

4.56 (41) (41) 4.56 217 (20) (20) 217 428 (39) (39) 428

40.5 (42) (42) 40.5 2.54 (27) (27) 2.54 297 (31) (31) 297

78 (29) (29) 78 84 (31) (31) 84 110(40) 110(40)

618 (26) (26) 618 4.58 (19) (19) 4.58 1:3:3 (6) (6) 1:3:3 419 (18) (18) 419

11 (18) (18) 11 11 (18) (18) 11 (2) 11 (2) (14) 99 (14)

288 288 196 196 76 76 182 182

(26) (26) (18) (18) (7) (7) (17) (17)

2.53 (27) (27) 2.53 206 (22) (22) 206 41 (4) (4) 41 17.5 (18) (18) 17.5

66 (24) (24) 66 44 (16) (16) 44 1.5 (6) (6) 1.5 .53 (20) (20) .53

1042 (44) (411') 1042 3620.5) 3620.5) 781 (33) (33) 781 ,520 (22) (22) ,520 2,5 (4) (4) 2,5 192 (8) (8) 192

10 (16) (16) 10 0(0) 0(0) 26 (41) (41) 26 (10) 66 (10) 17 (1) (1) 17 (13) 88 (13)

442 (40) (40) 442 127 (12) (12) 127 39.5 (36) (36) 39.5 208 (19) (19) 208 23 (2) (2) 23 94 (9) (9) 94

449 (47) (47) 449 1.5.5 (16) (16) 1.5.5 288 (30) (30) 288 (2.5) 236 (2.5) 236 27 (1) (1) 27 67 (7) (7) 67

141 (.52) (.52) 141 80 (29) (29) 80 72 (27) (27) 72 70 (26) (26) 70 33 (4) (4) 33 23 (9) (9) 23

1282 (.53) (.53) 1282 481 (20) (20) 481 494 (21) (21) 494 13.5 (6) (6) 13.5

31 (49) (49) 31 7(11) 7(11) 1:3 (21) (21) 1:3 12 (19) (19) 12

.570 (,52) (,52) .570 231 (21) (21) 231 229 (21) (21) 229 71 (6) (6) 71

.516 (.54) (.54) .516 197 (21) (21) 197 196 (20) (20) 196 47(.5) 47(.5)

16.5 (61) (61) 16.5 46 (17) (17) 46 26 (20) (20) 26 (2) .5.5 (2)

719 (30) (30) 719 1026 (43) (43) 1026 640 (27) (27) 640 (2.5) 602 (2.5) 602 .502 (21) (21) .502 1,021 (43) (43) 1,021 937 (39) (39) 937 307 (13) (13) 307

12 (19) (19) 12 1.5(24) 1.5 (24) 11 (18) (18) 11 12 (19) (19) 12 10 (16) (16) 10 18 (29) (29) 18 :30 (48) (48) :30 (10) 66 (10)

298 (27) (27) 298 4.57 (42) (42) 4.57 264 (24) (24) 264 271 (2.5) (2.5) 271 218 (20) (20) 218 434 (39) (39) 434 431 (39) (39) 431 134 (2) (2) 134

31.5 (33) (33) 31.5 408 (43) (43) 408 278 (29) (29) 278 242 (2.5) (2.5) 242 214 (22) (22) 214 (4.5) 432 (4.5) 432 37.5 (.39) (.39) 37.5 129 (14) (14) 129

94 (3.5) (3.5) 94 146 (.54) (,54) 146 87 (32) (32) 87 77 (28) (28) 77 60 (22) (22) 60 1:37(.50) 1:37 (.50) 101 (:37) (:37) 101 38 (14) (14) 38

0.02 0.02 <0.001 <0.001 (l.O04 0.004 0.41 0.41 0.36 0.36 0.001 << 0.001 0..50 0..50 0.63 0.63

20.5 (9) (9) 20.5 308 (13) (13) 308

(13) 88 (13) 10 (16) (16) 10

98 (9) (9) 98 1.50(14) 1.50(14)

78 (8) (8) 78 117 (12) (12) 117

21 (8) (8) 21 31 (11) (11) 31

0..58 0..58 0.,59 0..59

Value PP Value 0.001 << 0.001 0.001 << 0.001 (WOl << (WOl

0.41 0.41 0,09 0,09 0,04 0,04 0,.51 0,.51 0,001 << 0,001 0,001 << 0,001 0.002 0.002 0.001 << 0.001 (W01 << (W01 0.30 0.30 0.001 << 0.001

are given given as as No. No. (%), (%), unless unless otheJWise otherwise indicated. indicated. AAA AAA = = abdominal abdominal aortic aortic surgel),; surgel)'; CEA CEA = = carotid carotid endarterectomy; endarterectomy; LLR LLR = = lower lower limb limb *Values are *Values reconstruction. arterial reconstmction. arterial f Values given given as as mean mean (SD). (SD). tValues [Previous coronary coronary artery artery bypass bypass graft graft or or percutaneous percutaneous coronary coronary intervention. intervention. tPrevious

weight group, group, patient patient in in the the obese obese group group had had more more weight cases of of hypertension, hypertension, DM, DM, and and dyslipidemia, dyslipidemia, and and cases were more more likely likely to to be be treated treated with with l3-blockers, l3-blockers, were statins, aspirin, aspirin, and and ACE ACE inhibitors inhibitors (p (p < < 0.05 0.05 for for all). all). statins, During follow-up, follow-up, 1,048 1,048 patients patients (43,8%) (43,8%) died; died; During 56.8% of of them them had had COPD. COPD. Mortality Mortality among among patients patients 56.8% in different different BMI BMI categories categories included included 34 34 patients patients in (54%) in in the the underweight underweight group, group, .550 .550 patients patients (50%) (50%) (54%) in the the normal normal group, group, 380 380 patients patients (40%) (40%) in in the the in overweight group, group, and and 83 83 patients patients (31%) (31%) in in the the overweight obese group group (p (p < < 0.001), 0.001), obese The relationships relationships among among BMI BMI categories categories and and The COPD classifications classifications are are shown shown in in Figure Figure 1. 1. The The COPD prevalence of of COPD COPD showed showed an an inverse inverse relationship relationship prevalence with BMI; BMI; COPD COPD was was present present more more often often in in patients patients with with lower lower BMI BMI (p (p < < 0.001). 0.001). The The percentage percentage of of with www.chestjournal.orq www,chestjournai.org

COPD was was highest highest in in patients patients who who were were underunderCOPD weight (51%), (51%), which which was was largely largely driven driven by by the the weight increased prevalence prevalence of of severe severe COPD COPD in in this this group. group. increased In the the underweight underweight category, category, 19% 19% of of the the patients patients In had severe severe COPD; COPD; whereas, whereas, in in the the obese obese categOl), category had only 2% 2% of of the the patients patients had had severe severe COPD, COPD, only Moderate-to-severe COPD COPD was was independently independently asasModerate-to-severe sociated with with increased increased mortality mortality (moderate (moderate COPD: COPD: sociated HR, 1.67; 1.67; 95% 95% CI, CI, 1.42 1.42 to to 1.97; 1.97; severe severe COPD: COPD: HR, HR, HR, 1.96; 95% 95% CI, CI, 1.50 1.50 to to 2,55) 2,55) [Table [Table 2]. 2]. BMI, BMI, on on the the 1.96; other hand, hand, was was inversely inversely associated associated with with mortality, mortality, other The risk risk of of mortality mortality increased increased by by 4% 4% for for each each 11 The kglm22 reduction reduction in in BMI. BMI. After After adjusting adjusting for for the the kglm cardiac risk risk score, score, age, age, gender, gender, year year of of surgery, surgery, cardiac current smoking smoking status, status, and and use use of of pulmonary pulmonary drugs, drugs, current patients who who were were underweight underweight were were 1.42 1.42 times times patients CHEST /134/5/ /134/5/ NOVEMBER. NOVEMBER. 2008 2008 CHEST

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14 They et al. They studied studied the the with those those of of Landbo Landbo et al. 14 with prognostic association association of of BMI BMI in similar population population prognostic in aa similar of COPD COPD patients patients and and observed observed that that underweight underweight of patients, especially especially those those with with severe severe COPD, COPD, had had an an patients, increased risk risk of of mortality. mortality. increased Since spirometry spirometry is is generally generally not not part part of of aa normal normal Since preoperative assessment assessment for for patients patients who who are are underunderpreoperative going major major vascular vascular surgery surgery at at many many institutions, institutions, going COPD may may remain remain undiagnosed undiagnosed and and untreated untreated in in COPD this group group of of patients, patients, resulting resulting in in excess morbidity this excess morbidity and mortality. mortality. Indeed, Indeed, even in our our population, population, only only and even in 9% of of the the cohort cohort was was taking bronchodilators, though though 9% taking bronchodilators, the overall overall prevalence prevalence of of COPD COPD was was 47% 47% and and that that the for moderate-to-severe moderate-to-severe COPD COPD was was 27%. 27%. The The findfindfor ings in in this this study study highlight highlight the the need need for for more ings more aggressive use use of of spirometry and the the institution institution of of aggressive spirometry and COPD interventions interventions (including (including smoking smoking cessation, cessation, COPD treatment of of exacerbations, the use use of of maintemaintetreatment exacerbations, and and the nance drugs) drugs) for for patients patients with with peripheral peripheral vascular vascular nance disease. disease. The mechanisms mechanisms responsible responsible for for the the inverse inverse relarelaThe tionship between between BMI BMI and and mortality mortality are are uncertain. uncertain. tionship l5 ,16 have Previous studies studies l5,16 have suggested suggested that that underunderPrevious weight patients patients demonstrate demonstrate aa higher higher metabolic metabolic rate, rate, weight lower antioxidant antioxidant capacity capacity in in skeletal skeletal muscles, muscles, and lower and increased which increased systemic systemic inflammatory inflammatory responses, responses, which may contribute to loss and and morbidity. may contribute to excess excess weight weight loss morbidity. Underweight been associated associated with with Underweight status status has has also also been Our study study findings findings sugsugovert or or occult occult malignancy. malignancy. Our overt gest that that in in addition addition to to the the above above factors, factors, COPD COPD may may gest also be the obesity obesity paradox paradox (in (in the the also be responsible responsible for for the low BMI categories). low BMI categories). Our finding finding that that overweight overweight and and obesity obesity are are assoOur associated with with improved improved survival survival is is consistent consistent with with the the ciated obesity paradox paradox of of survival survival in in HF HF patients. patients. Previous Previous obesity studies have have clearly clearly demonstrated demonstrated that that HF HF patients patients studies 17,18 who have have aa higher percentage of ,18 and and who higher percentage of body body fat fat 17 elevated BMp9,20 BMp9,20 have have lower lower mortality mortality than than those those elevated reduced BMIs. BMIs. However, However, the the mechmechwith normal normal or or reduced with anism responsible responsible for for this this observation observation remains remains elueluanism 21 ,22 Some sive.21,22 Some investigators investigators have have suggested suggested223-25 that sive. 3-25 that increased BMI BMI may may confer confer protection protection against increased against endoendothe toxin inflammatory cytokines cytokines by by increasing increasing the toxin and and inflammatory

t:::J No COPD t:::JMlld

COP~

_Moderate COPD _Severe

COP~

.....5

The cross-relationship cross-relationship between between corD corD stahls status and EMI EM! FIGURE 1. 1. The in our our population: population: corD COrD classifications classifications among among EMI categories. in EMI categories.

more of normal normal weight weight more likely likely to to die die than than individuals individuals of (HR, 1.42; 1.42; 95% CI, 1.00 1.00 to to 2.01). In contrast, contrast, (HR, 95% CI, 2.01). In overweight and and obese obese individuals had aa reduced reduced risk risk overweight individuals had of mortality 0.73; 95% 95% CI, CI, of mortality (overweight (overweight patients: patients: HR, HR, 0.73; 0.64 to to 0.84; 0.84; obese obese patients: patients: HR, HR, 0.68; 0.68; 95% 95% CI, CI, 0.53 0.53 0.64 to 0.86) 0.86) [Table [Table 3, model 4]. 4]. When When COPD COPD severity severity to 3, model was added added to to the the multivariate the relationship relationship was multivariate model, model, the between underweight underweight status status and and mortality mortality no no longer longer between remained statistically statistically significant significant (HR, (HR, 1.29; 1.29; 95% 95% CI, CI, remained 0.91 to to 1.93). 1.93). However, However, obesity obesity and and overweight overweight 0.91 remained significantly significantly related related to to mortality mortality (Table (Table 3, 3, remained model 5). 5). model

DISCUSSION DISCUSSION

In this of In this study, study, we we examined examined aa large large cohort cohort of patients with with PAD and found found aa high prevalence of of patients PAD and high prevalence COPD (46.4%), (46.4%), especially among patients patients who who were were COPD especially among underweight. We We observed observed an an inverse inverse relationship relationship underweight. between BMI BMI and and mortality, mortality, which which is is consistent consistent with with between the obesity obesity paradox paradox described described previously. previously. However, However, the when we we adjusted adjusted for for COPD COPD and and its its severity, the when severity, the relationship between between underweight underweight and and mortality mortality no no relationship longer remained remained significant, significant, indicating indicating that that aa subsublonger stantial of the the excess excess deaths deaths in in patients patients stantial proportion proportion of with low low BMI BMI occur occur in in subjects subjects with with COPD. COPD. This This with raises the possibility possibility that that the the excess raises the excess deaths deaths in in papatients the patients' patients' tients with with low low BMI BMI are are related related to to the underlying COPD. COPD. Our Our results results are are in in accordance accordance underlying

Table 2-Relationship 2-Relationship Between Between Baseline Baseline Risk Risk Factors Factors and and All-Cause All-Cause Mortality Mortality Table Univariate Analysis Analysis Univariate Variables Variables COPDt COPDt Mild Mild Moderate Moderate Severe Severe BMI BMI

II

HR HR

95% CI 95% CI

1.45 1.45 2.21 2.21 2..52 2..52 0.95 0.95

1.23-1.71 1.23-1.71 1.91-2.56 1.91-2.56 1.99--3.18 1.99--3.18 0.94-0.97 0.94-0.97

Multivariate Analysis* Analysis* Multivariate P P Value Value

< < < < < < < <

0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.001

II

II

HR HR

95% CI CI 95%

P Value Value P

U8 1.18 1.67 1.67 1.96 1.96 0.96 0.96

1.00--1.40 1.00--1.40 1.42-1.97 1.42-1.97 1.50--2.55 1.50--2.55 0.94-0.98 0.94-0.98

< 0.001 0.001 < < 0.001 0.001 < < 0.001 0.001 <

II

0,053 0,053

current smoking smoking status, status, year year of *Adjustments were were made made for gender, cardiac cardiac risk risk score, score, current of surgery, surgery, and and use use of of pulmonary pulmonary medication. medication. *Adjustments for age, age, gender, lI [Classiflcation COPD according according to to the the Global Global Initiative Initiative for for Chronic Chronic Obstructive Obstructive Lung Lung Disease Disease (or (or GOLD) GOLD) c1assification. classification.'! tClassification of of COPD

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Table Severity and and Mortality* Mortality* Table 3-Association 3-Association Between Between BMI BMI (Continuous (Continuous and and Categories) Categories) and and COPD COPD Severity Variahles

Modell

Model 22

Model 33

Model 44

ModelS

Cases, No. Patients alive, No. BM! Underweight Overweight Obese capo Mild capo capo Moderate capo capo Severe capo

2,387 2,387 1,340 1,340 0.95 0.95 (0.94--0.97) (0.94--0.97) 1.38 1.38 (0.98-1.96) (0.98-1.96) 0.73 (0.64-0.8,3) (0.64-0.8,3) 0.73 0.68 0.68 (0.54-0.85) (0.54-0.85) 1.19 1.19 (1.01-1.41) (1.01-1.41) 1.81 1.81 (1.55-2.10) (1.55-2.10) 2.11 2.11 (1.67-2.68) (1.67-2.68)

2,387 2,387 1,340 1,340 0.95 0.95 (0.94--0.97) (0.94--0.97) 1.44 1.44 (1.02-2.04) (1.02-2.04) 0.73 (0.64--0.83) 0.73 (0.64--0.83) 0.67 0.67 (0.53-0.85) (0.53-0.85)

2,387 2,387 1,340 1,340 0.96 0.96 (0.94-0.97) (0.94-0.97) 1.30 (0.92-1.40) 1.30 (0.92-1.40) 0.73 (0.64--0.84) (0.64--0.84) 0.73 0.67 0.67 (0.53-0.85) (0.53-0.85) 1.19 1.19 (1.00-1.41) (1.00-1.41) 1.69 1.69 (1.43-1.99) (1.43-1.99) 1.97 1.97 (1.51-2.57) (1.51-2.57)

2,387 2,387 1,340 1,340 0.96 0.96 (0.94--0.97) (0.94--0.97) 1.42 (1.00-2.01) (1.00-2.01) 1.42 0.73 (0.64--0.84) (0.64--0.84) 0.73 0.68 0.68 (O.53-D.86) (O.53-D.86)

2,387 2,387 1,340 1,340 0.96 (0.94-0.97) (0.94-0.97) 0.96 1.29 1.29 (0.91-1.93) (0.91-1.93) 0.74 0.74 (0.65-0.84) (0.65-0.84) 0.68 (0.54--0.86) 0.68 (0.54--0.86) 1.18 1.18 (1.00-1.40) (1.00-1.40) 1.67 1.67 (1.42-1.97) (1.42-1.97) 1.96 1.96 (1.50-2.55) (1.50-2.55)

= adjusted for age and gender; gender; Model 22 = = multivariate analysis analysis in in *Values are given as the the HR (95% (95% CI), unless otherwise indicated. Modell = of surgery, and and pulmonary medication medication used; Model 3 == multivariate which adjustments were made for age, gender, cardiac risk score, year of capo severity; Model 44 == multivariate analysis analysis in which analysis in which adjustments were were made made for all of the the variables in model 22 plus capo analysis of the the variables in model 2 adjustments were made for all of 2 plus cigarette smoking; Model 55 == multivariate analysis in which adjustments were capo severity. made for all of the variables in model tIl,odel 22 plus cigarette smoking and capo

production of of "buffering" "buffering" lipoproteins. lipoproteins. HF HF may may be production be diagnosed diagnosed in in obese obese patients patients at at an an earlier earlier stage stage bebecause tend to to be be more more symptomatic HF cause they they tend symptomatic than than HF patients with with lean lean body body mass. mass. Thus, may patients Thus, obesity obesity may Simply marker for for less less severe severe HF. HF. simply be be aa marker Our finding finding that that nearly nearly ,50% ,50% of of patients patients undergoundergoOur ing major major vascular vascular surgery surgery for for PAD PAD had had COPD COPD ing highlights the the importance importance of of using using screening screening spiromspiromhighlights etry in in this this population. population. Over Over half half of of these these patients patients in in etry the underweight underweight category category had had moderate-to-severe moderate-to-severe the COPD. These These data data support support the the notion notion of of more more COPD. aggressive "screening" "screening" and and treatment treatment for for COPD COPD aggressive before and and after after surgery surgery to to optimize optimize the the health health before outcomes of outcomes of these these patients. patients. There There were were certain certain limitations limitations to to the the study. study. BMI BMI has been been recently recently questioned questioned as has as aa sensitive sensitive measure measure 26 Other fatness.P" Other anthropometric anthropometric measuremeasureof of body body fatness. ments of of body body fat fat such such as as waist waist circumference circumference were were ments not routinely routinely performed performed preoperatively preoperatively and, and, hence, hence, not could not not be be included included in in our our analysis. analysis. We We also also did did not not could have complete complete lung lung function function measurements measurements for for the the have cohort. Knowledge Knowledge regarding regarding total total lung lung and and inspirainspiracohort. tory capacity capacity as tory as well well as as diffusing diffusing capacity capacity may may proprovide vide incremental incremental information information on on mortality. mortality. MoreMoreover, directly interview interview patients, patients, over, because because we we did did not not directly we could separate out out purposeful purposeful from from nonpurwe could not not separate nonpurposeful 10ss.27 Thus, Thus, the the underlying underlying reasons reasons poseful weight weight 10ss.27 for the the low for low BMI BMI in in our our population population are are unknown. unknown. Finally, Finally, because because smoking smoking is is aa more more powerful powerful risk risk factor factor in in PAD PAD patients patients than than in in patients patients with with HF, HF, ischemic ischemic heart heart disease, disease, or or stroke, stroke, it it is is uncertain uncertain whether whether our our current current findings findings can can be be generalized generalized to to other other cardiovascular cardiovascular populations. populations.

COPD and and that BMI was related to to longlongCOPD that BMI was inversely inversely related term mortality. Importantly, there there was was aa dispropordisproporterm mortality. Importantly, tionate of COPD COPD in in patients patients with with tionate overrepresentation overrepresentation of low Patients with with low low BMI BMI had had an an increased increased low BMI. BMI. Patients risk of of mortality, mortality, while while obese obese and and overweight overweight paparisk tients had had aa reduced reduced risk risk of of mortality mortality compared compared to to tients individuals of of normal normal weight. weight. Adjustments Adjustments for for the the individuals severity of of COPO CO PO abolished abolished the the significant significant relationseverity relationship between between BMI BMI and ship and mortality mortality in in those those patients patients who but not not in in those who were were underweight underweight but those who who were were overweight or obese. obese. These These data data suggest COPD overweight or suggest that that COPD is highly prevalent prevalent condition condition in in PAD PAD patients patients who who is aa highly are undergOing undergoing surgical surgical procedures, procedures, and and that that COPD COPD are may be be responsible responsible for for the the obesity obesity paradox may paradox associassociated with with reduced reduced BMI BMI and and mortality mortality in in patients patients ated with PAD. PAD. with

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5 5

CONCLUSION CONCLUSION

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